Development of optically active radioligand for in vivo investigation of brain nicotine receptors.

开发用于脑尼古丁受体体内研究的光学活性放射性配体。

• 批准号: 06672142
• 负责人: SAJI Hideo
• 金额: $ 1.34万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06672142/
• 关键词: nicotine receptor; optical isomer; radiopharmaceutical; brain; radioiodine; nuclear medicine; biodistribution; radioreceptor assay; 放射性医薬品; アルツハイマー病; 老化; 病態モデル動物; 核医学診断

Changes in the density of nicotine receptors have recently been reported in the brains of patients with various disorders, including Alzheimer's disease. These obsevations have stimulated interest in means of imaging the distribution of brain nicotinic receptors noninvasively in vivo with nuclear medicinal imaging techniques such as SPECT.In this study, the superior radiation properties of 123-I for SPECT prompted us to synthesize a radioiodinated nicotine analog with high receptor affinity. Thus, (S) 5-iodonicotine (INC), an (S) -nicotine analog iodinated at the 5-position of the pyridine ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain nicotine receptors by SPECT.[125I] - (S) -INC was synthesized with high specific radioactivity. The binding data of INC for brain nicotine receptors revealed that the affinity of INC was the same as that of (S) -nicotine and 80-fold higher than the (R) -enantiomer. Biodistribution studies in mice disclosed that the brain uptake of INC was rapid and profound. Regional cerebral distribution studies in rats by autoradiography disclosed that the accumulation of [125-I] -INC was correlated well with the distribution of nicotine receptors reported from in vitro studies. (R) -enantiomer showed more rapid washout the brain and smaller regional cerebral distribution than (S) -enantiomer. Thus, INC bound to brain nicotine receptors in vivo and therefore 123-I-INC may be a potential radioligand for use in in vivo cerebral nicotinic receptor studies by SPECT.

最近有报道称，包括阿尔茨海默病在内的各种疾病患者的大脑中都存在尼古丁受体密度的变化。这些研究激发了人们对利用SPECT等核医学成像技术无创性地在活体内成像脑内尼古丁受体分布的兴趣。在本研究中，123-I用于SPECT的优越的辐射特性促使我们合成了一种具有高受体亲和力的放射性碘化尼古丁类似物。因此，合成了一种位于吡啶环5-位上的(S)-尼古丁类似物--(S)-5-碘烟碱，并用SPECT对其进行了放射性评价，合成了具有高比放射性的[~(125)I]-(S)-烟碱类似物。INC与脑尼古丁受体的结合数据表明，INC与(S)-尼古丁的亲和力相同，而比(R)-对映体高80倍。在小鼠体内的生物分布研究表明，Inc.在大脑中的摄取迅速而深刻。放射自显影在大鼠脑内的局部分布研究表明，[125-I]-Inc的蓄积与体外研究中报道的尼古丁受体的分布有很好的相关性。(R)-对映体比(S)-对映体具有更快的脑组织洗脱速度和更小的局部脑分布。因此，Inc.在体内与脑尼古丁受体结合，因此123-I-Inc.可能是一种潜在的放射性配基，用于SPECT体内脑尼古丁受体的研究。

项目成果

S.R.Choi, et al.: "The potential uses of animal PET in the assessment of drug effect : evaluation of the effects of nicotine and ginsenoside Rb1." J.Label.Compd.Radiopharm.35. 170-171 (1995)

S.R.Choi 等人：“动物 PET 在药物效果评估中的潜在用途：评估尼古丁和人参皂苷 Rb1 的效果。”

渡辺 章: "Synthesis and in vivo evaluation of (S)-(E)-5-(2-iodovinyl)nicotine: a new nearonal nicotinic cholinergic receptor imaging agent for SPECT." J. Label. Compd. Radiopharm.35. 382-383 (1995)

Akira Watanabe：“(S)-(E)-5-(2-碘乙烯基)尼古丁的合成和体内评估：一种用于 SPECT 的新型烟碱胆碱能受体成像剂。J. Label.35。” -383 (1995)

Hideo Saji: "Radiodinated Nordiazepam analog for in vivo assessment of Benzodiazepine Receptors by single photon emission tomography" Nucl Med.Biol.21. 57-62 (1994)

Hideo Saji：“通过单光子发射断层扫描对苯二氮卓受体进行体内评估的放射性去甲西泮类似物”Nucl Med.Biol.21。

佐治英郎: "Radioiodinated nordiazepam analog for in vivo assessment of bengediagepine receptors by single photon emissior tomogryohy." Nucl. Med. Biol.21. 57-62 (1994)

Hideo Saji：“用于通过单光子发射断层扫描进行体内评估的放射性去甲西泮类似物”，《Nucl Biol》。

Akira Watanabe, et al.: "Synthesis and in vivo evaluation of (S) - (E) -5- (2-iodovinyl) nicotine : a new neuronal nicotinic cholinergic receptor imaging agent for SPECT." J.Label.Compd.Radiopharm.35. 382-383 (1995)

Akira Watanabe 等人：“(S) - (E) -5- (2-碘乙烯基) 尼古丁的合成和体内评估：一种用于 SPECT 的新型神经元烟碱胆碱能受体成像剂。”